How does exercise counteract stress-induced tumor growth? Increased physical activity following the diagnosis of cancer has been demonstrated to significantly reduce cancer recurrence. Furthermore, exercise has been demonstrated to have antidepressant effects, benefiting individuals who are chronically stressed, including ovarian cancer patients. Because chronic stress contributes to aggressive tumor growth, resulting in a poor outcome for cancer patients, we predict that changes in behavior that reduce chronic stress should also prevent stress-induced tumor growth. We propose that exercise improves the overall survival of cancer patients by acting as an antidepressant, and hypothesize that the same molecular pathways activated by exercise and antidepressants that reduce stress, will also inhibit stress- mediated tumor growth. We further predict that these effects are modulated by the circuits inside the cells that are affected by a substance called BDNF. This substance is frequently produced in response to either antidepressant drugs or exercise and is required for antidepressant behavioral effects. AIM 1. To determine the effects of exercise and antidepressants on stress-induced ovarian tumor growth in mice, and to determine if these effects are mediated by the BDNF/TrkB pathway. We have already shown that both regular exercise and antidepressants can reverse stress-mediated tumor growth in our mouse model of ovarian cancer. We first plan to confirm these findings with additional ovarian tumor types. To determine if BDNF/TrkB signaling impacts ovarian tumor growth, we will evaluate changes in circulating proBDNF and mBDNF levels in stressed mice in response to exercise and antidepressants. We will further attempt to correlate plasma levels of proBDNF and mBDNF to tumor growth and metastasis in exercising and antidepressant-treated animals, who are exposed to daily stress. We expect that increasing levels of mBDNF in response to exercise or antidepressants should be reflected by smaller, less aggressive tumors. AIM 2. To determine the effects BDNF/TrkB activation in ovarian cancer cells: We have shown that the BDNF precursor protein, proBDNF, is secreted by ovarian cancer cell lines and tumors. Exercise and antidepressants result in the conversion of proBDNF to mature BDNF (mBDNF), and the two molecules are thought to produce opposing effects on cell growth and behavior. The receptors for these two molecules, p75NTR and TrkB respectively, are also expressed by ovarian tumors. We will characterize changes in ovarian cancer cell growth and spread in response to proBDNF versus mBDNF in cultured cells. We anticipate that the response of cultured cells to proBDNF and mBDNF will reflect the response of tumors to exercise and antidepressants in an animal model of ovarian cancer. In keeping with the goals of "Exploratory Grants for Behavioral Research in Cancer Control" we anticipate that these experiments may clarify the biological mechanisms underlying the beneficial effects of exercise on cancer progression and recurrence. PUBLIC HEALTH RELEVANCE: In this proposal, we hope to unravel the molecular biology underlying how exercise reduces cancer recurrence. Changes in behavior can have a significant impact on patient survival and quality of life following the diagnosis of cancer. By counteracting the effects of stress, exercise could significantly improve the clinical outcome of ovarian cancer patients. Furthermore, in patients fatigued and stressed by chemotherapy, antidepressants may provide a substitute for the beneficial effects of exercise until physical activity can be comfortably resumed. An understanding of the mechanisms responsible for the beneficial effects of exercise may lead to the development more effective treatment strategies, which will improve the quality of life for all cancer patients.